Oxazolidinones represent a novel chemical class of synthetic antimicrobial agents. Linezolid represents the first member of this class to be used clinically. Oxazolidinones display activity against important Gram-positive human and veterinary pathogens including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci (VRE) and β-lactam Resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria, Gram-positive and Gram-negative anaerobes. (Diekema D J et al., Lancet 2001; 358: 1975-82).
Limitations of oxazolidinones have also surfaced. They are inactive against Enterobacteriaceae (Zhanel, G G et al., Canadian Journal of Infectious Diseases, 2001, 12:379-390). Moreover, their potency for atypical respiratory pathogens such as Mycoplasma pneumoniae, M. hominis, Ureaplasma urealyticium and Chlamydia species is of a borderline range which could result in unacceptable clinical efficacy for the treatment of respiratory tract infections (Diekema D. J. et al. Lancet 2001; 358:1975-82).
Other limitations, that have appeared through the clinical development studies and use of linezolid and its potential successors in development, are that this class of compounds have a propensity to induce myelosuppression with consequent thrombocytopenia (Kuter D J et al., Pharmacotherapy, 2001: 21: 1010-1030).
Inhibition of monoamine oxidase by oxazolidinones has prompted clinical use of the members of this class with concomitant usage of adrenergic or serotonergic agents and selective serotonin reuptake inhibitors (Ament P W et al., Am Fam Physician 2002, 65: 663-70). Furthermore, due to short half-life, linezolid has b.i.d dosing regimen.
There are several references disclosing antibacterial activity of oxazolidinones. For example, International (PCT) publication WO 95/25106 discloses substituted piperidino phenyloxazolidinones. International (PCT) publication WO 96/13502 discloses phenyloxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety. U.S. Patent application 04/0063954, International (PCT) publications WO 04/007489 and WO 2004/007488 disclose piperidinyl phenyl oxazolidinones for antimicrobial use. Pyrrodinyl/piperidinyl phenyl oxazolidinone antibacterial agents are also described in Kim H Y et al., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230. International (PCT) publication WO 96/35691 discloses spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinone derivatives where one of the hetero atoms in the ring is nitrogen. Diazepeno phenyloxazolidinone derivatives are disclosed in the International (PCT) publication WO 99/24428. International (PCT) publication WO 02/06278 discloses substituted aminopiperidino phenyloxazolidinone derivatives.
International (PCT) publications WO 04/007488 and WO 04/007489 disclose a novel series of oxazolidinones, which show increased potency, having bactericidal activity, in contrast to the earlier-described bacteriostatic activity of linezolid and literature described oxazolidinones. Unusual bactericidal activity is shown to be displayed not just against linezolid-sensitive strains but also for the first time against linezolid-resistant strains, thus indicating a differential binding at conventional site/s of the ribonucleoprotein and/or targeting multiple such receptor sites. International (PCT) publication WO 05/054234 discloses geminally disubstituted piperidine phenyloxazolidinones derivatives having improved in vivo efficacy.
The compounds, of the present invention have improved therapeutically favorable pharmacokinetic profile amenable for the development of once a day dosing oxazolidinone. The compounds of the invention thus establish their ability to give in vivo protection to animals and be useful clinically.